Long-Term Consequences of Drugs on the Paediatric Cardiovascular System

Abstract

Many pharmacological and toxicological actions of drugs in children cannot be fully predicted from adult clinical experience or from standard non-clinical toxicology studies. Numerous drugs have direct or indirect pharmacological effects on the heart and are prescribed for children of all ages. Toxicity or secondary effects may be immediate or delayed for years after drug exposure has ceased. Originally, the aim of this review was to compile information on the effect of specific drugs on the post-natal development of the cardiovascular system and to examine long-term follow-up of the use of cardio-active drugs in children. The limited database of published information caused the original question to evolve into an examination of the medical literature for three areas of information: (i) whether vulnerable developmental windows have been identified that reflect the substantial functional development that the cardiovascular system undergoes after birth; (ii) what is known about pharmacological perturbation of development; and (iii) what the likelihood is of drug exposure during childhood. We examined different scenarios for exposure including random, isolated exposure, conditions historically associated with adults, primary or secondary cardiac disease, psychiatric and neurological conditions, asthma, cancer and HIV. Except for random, isolated drug exposures, each category of possible exposure contained numerous drugs known to have either primary or secondary effects on the cardiovascular system or to influence factors associated with atherosclerosis. It is likely that a significant number of children will be prescribed drugs having either direct or indirect effects upon the immature cardiovascular system. A confounding factor is the simultaneous use of over-the-counter medications and herbal or nutraceutical preparations that a patient, parent or guardian does not mention to a prescribing physician. Metabolism is also important in assessing drug effects in children. Differences in body water : body fat ratio, age-related gastrointestinal absorption, distribution, excretion, renal function and drug metabolizing capabilities make it possible for children to have a different metabolite profile for a drug compared with adults. There is little examination of drug effects on the interdependent processes of cardiac maturation and less examination of metabolite effects. It is difficult to identify delayed toxicities in children as these adverse events may take years to manifest with many patients lost to follow-up. Clearly this is an area of study where intermediate endpoints and surrogate markers would be of great benefit. Pharmacogenomics may be useful in providing markers of increased risk or susceptibility. A perspective must be kept in balancing the possibility of a problem with the very real benefits that many children experience from the use of these pharmaceuticals.

Researching asthma across the ages: Insights from the National Heart, Lung, and Blood Institute’s Asthma Network

“…Due to the logistical constraints of any clinical trial, the evaluation of the long-term effects of an intervention, positive or negative, can be challenging (62). Cross-age studies that include behavioral and educational interventions can potentially also have long-term spill-over effects on family management or self-management of other chronic conditions (63).…”

Pediatric Polypharmacy

“…Therapy with medications started in childhood for management of chronic conditions often continues for decades—well beyond the duration of any drug approval trials and thus well outside our understanding of potential drug effects. 11,12 As we advance the research agenda of pediatric polypharmacy, it is important to consider this broad trend and to move forward with studies on the effects of long-term polypharmacy in children. Outcomes studies will depend on high-quality administrative data.…”

The Impact of Exercise on Cardiotoxicity in Pediatric Cancer Survivors: A Scoping Review Protocol

“…A significant long-term health issue for childhood and adolescent cancer survivors (CACS) is a heightened cardiovascular disease risk due to cancer therapy (Bansal et al, 2014;Hausner et al, 2008). CACS who receive cardiotoxic cancer therapies, such as anthracyclines and chest-directed radiation therapy, experience a greater risk of heart dysfunction and cardiovascular disease (CVD) later in life (Armenian et al, 2018;Chow et al, 2019;Hausner et al, 2008;Lipshultz et al, 2013;McGowan et al, 2017). Specifically, the longterm impact of cardiotoxic treatments on the heart includes decreased left ventricular (LV) mass, wall thickness, contractility, and fractional shortening (Scott et al, 2011).…”